RESUMEN
Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety. The reason for this disparity is unclear, but may result from a differential response to adjuvant chemotherapy. We examined known molecular markers for response to common chemotherapy in these two histological subtypes. In all, 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome. Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed. Quantitative expression levels of drug pathway genes were determined using TaqMan RT-PCR (5-fluorouracil (5-FU): TYMS, DPYD, ECGF1; oxaliplatin: GSTP1 (glutathione S-transferase pi), ERCC1 and 2; irinotecan: ABCB1, ABCG2, CYP3A4, UGT1A1, CES2, TOP1). Mucinous tumours significantly overexpressed both TYMS and GSTP1 relative to nonmucinous tumours and patient-matched normal mucosa. No significant differences in expression of the remaining markers were found. Mean follow-up was 20 months; 17 patients had recurrent disease. Among patients receiving 5-FU, those with mucinous tumours experienced shorter disease-free survival (DFS) than those with nonmucinous tumours (median DFS 13.8 vs 46.5 months, P=0.053). Mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. Likewise, DFS may be decreased in patients with mucinous tumours who receive 5-FU. The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer.
Asunto(s)
Adenocarcinoma Mucinoso/metabolismo , Biomarcadores de Tumor/análisis , Camptotecina/análogos & derivados , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Anciano , Camptotecina/farmacología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Cartilla de ADN , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/farmacología , Humanos , Irinotecán , Masculino , Compuestos Organoplatinos/farmacología , Oxaliplatino , Pronóstico , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Previous research suggested that splanchnic hypoperfusion occurs after resuscitation with certain acellular hemoglobin solutions. We examined the influence of maltose content and oxygen affinity on resuscitation with various hemoglobin polyoxyethylene conjugate solutions after hemorrhage. METHODS: Fifteen swine underwent hemorrhage and equal volume resuscitation with pyridoxalated hemoglobin polyoxyethylene conjugate containing 0% or 8% maltose, or low P50 conjugate, which also contained 8% maltose. Five control animals were monitored but not bled. Regional blood flow was determined by using radioactive microspheres, gastric mucosal perfusion was estimated with tonometry, and gut histopathology was evaluated. RESULTS: All hemoglobin solutions produced vasoconstriction, manifested by elevated mean systemic and pulmonary artery pressures without a significant decrease in cardiac index compared with the sham group. Resuscitation with maltose-containing solutions elevated arterial and regional PCO2 and depressed arterial pH and gastric pHi (p < 0.05 for all). Splanchnic and renal blood flows were reduced in the low P50 + 8% maltose group (p < 0.05 vs. sham and baseline for renal blood flow), possibly indicating greater regional vasoconstriction in this group. Ileal mucosal damage was more severe in the maltose-containing groups and correlated with decreased pHi. CONCLUSION: Vasoconstriction occurred in all groups but was more severe in the low P50 + 8% maltose group. Maltose-containing solutions caused respiratory acidosis, decreased pHi, and histologic evidence of mucosal injury. Pyridoxalated hemoglobin polyoxyethylene conjugate without maltose was a superior resuscitation solution in this swine model.